More than three years after HIV/AIDS physicians began reporting an alarming trend of patients with high triglyceride levels, insulin resistance, accumulations of fatty tissue, and/or other alterations in body shape, the jury is still out on exactly what causes the phenomenon known as lipodystrophy or HIV-related adipose redistribution syndrome. In fact, after major studies in the United States, Australia and Europe, as well as three international workshops specifically addressing the problem, researchers have yet to arrive at even a common definition for the problem generally referred to as lipodystrophy.

Partly due to the lack of a standard set of defining criteria, the prevalence of lipodystrophy is one of the many unknowns surrounding the problem. "I could say it affects 20 percent of my caseload, someone else could say 80 percent, and we could mean the same thing," says Calvin Cohen, research director of Community Research Initiative of New England in Boston.

In a recent survey, 300 physicians with large HIV caseloads estimated that one in five of their patients had experienced lipodystrophy. The vast majority of the responding physicians (92 percent) defined the condition as a "maldistribution of body fat." Only 14 percent of the doctors identified lipid abnormalities as part of the problem, and only 3 percent pointed to diabetes. Agouron Pharmaceuticals, the sponsor of the survey, released the results during the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in Toronto in September 2000.

The survey also showed that attitudes are changing about what causes lipodystrophy. A survey two years ago found that nearly three-fourths of physicians believed protease inhibitors were to blame, but that number has declined to less than two-thirds. Among other contributing factors mentioned in the recent survey were nonnucleoside reverse transcriptase inhibitors (27 percent), nucleoside analogs (33 percent), the length of HIV infection (35 percent), and the amount of time on antiviral therapy (44 percent).

One in 10 physicians surveyed reported having patients with lipodystrophy who had never received antiretroviral treatment. Although it was not mentioned in the Agouron survey, studies indicate that lipodystrophy is more common in older patients with more advanced HIV disease.

The bottom line is that the syndrome--or syndromes--is "turning out to be far more complicated than anybody ever thought," says Kathy Mulligan, assistant professor of medicine at the University of California at San Francisco. "I think we've followed a lot of blind alleys over the past couple of years looking for easy answers. ... It's really emerging as one of the major complications of HIV and its therapies."

Those complications are becoming so widespread and well-known that physicians report an increasing number of newly tested people are refusing to initiate drug therapy due to fear of lipodystrophy. Reports are also common of patients who discontinue or consider discontinuing medications because they say the changes in their bodies affect their quality of life.

"I draw the line at humps," says Greg Harris, a long-term AIDS survivor, referring to the most dreaded symptom of lipodystrophy, the deposition of fat in the dorsocervical area--a phenomenon called "buffalo hump." A prominent Chicago AIDS activist who has been on antiviral therapy for 11 years, Harris says he has willingly endured "every other side effect--headaches, nausea, and diarrhea." But he would quit taking drugs if he developed physically disfiguring side effects, he says.

The buffalo hump problem is not only cosmetic, it can be clinically significant. Mulligan has seen buffalo humps so large they interfered with a patient's ability to breathe or sleep. In such extreme cases physicians have turned to liposuction, she says.

But while buffalo humps may be the most dramatic physical problem associated with lipodystrophy, patients are also deterred from treatment due to more commonly occurring problems, including accumulations of fat around the torso (truncal adiposity) and the loss of fat in the buttocks, limbs (peripheral lipodystrophy), and cheeks (facial fat atrophy). The latter, when severe, gives patients a hollow, skeletal look that they feel brands them as people with AIDS.

Unfortunately, fat distribution problems are more difficult to treat than the metabolic effects of lipodystrophy, which include insulin resistance and elevations in blood lipids. Those conditions respond to standard interventions that may not help with fat deposits and lipoatrophy. Doctors question whether the metabolic side-effects associated with HIV therapy even carry the same risk as their naturally occurring counterparts.

"Nobody has yet been able to show a short-term impact on either heart disease or other complications as a result of these lipid or glucose changes," Cohen says. "There's certainly no indication that these changes produce a rapid response. We don't know what the [long-term] impact is, because we don't have 30 years of these lipid changes to monitor."

Dealing with the physical maldistribution of fat is a more immediate problem. Working mostly in the dark, physicians are left to approach it on a case-by-case, trial-and-error basis. "The specific problems help determine what may be the most productive course," Mulligan says.

Changing therapies is the most obvious course open to physicians.

Cohen says he is intrigued by the fact that so far no research has linked lipodystrophy to nonnucleoside therapy. In Toronto he presented a study on patients using two nucleosides and one nonnucleoside reverse transcriptase inhibitor. The regimen dramatically reduced patients' viral loads and was well-tolerated, he says. Other researchers are exploring the use of a pair of nonnucleosides with one other drug, and Cohen hopes that combination may circumvent lipodystrophy problems. But at the same time he acknowledges that "the single most sobering conclusion is how little progress we have made so far in substituting one drug for another."

Switching to a protease-inhibitor-sparing regimen appears to help allay insulin and lipid-related problems, but that approach has not proved successful in reversing fat distribution abnormality, Mulligan says. If the fat problem is limited to central fat accumulation, exercise may help, she says, but it is unlikely to help if the problem involves loss of fat in the extremities.

Similarly, Serostim, recombinant human growth hormone, has proven useful helping patients shed fat, but if the patient also has a problem with peripheral fat loss, growth hormone will exacerbate it. Growth hormone also has the potential to cause glucose intolerance, so it is not recommended for people with clinically significant insulin resistance.

Metformin is sometimes helpful with diabetes and fat accumulation. But metformin causes fat loss everywhere, Mulligan adds, so, like Serostim, it has the potential to exacerbate peripheral fat loss. Another problem with metformin is that it can cause lactic acidosis, so people with increased lactate levels or impaired kidney function should not use the drug, Mulligan says. (Steven Grinspoon of Boston's Harvard Medical School has reported that lowering the dose may eliminate the problem of elevated lactates; in a study he conducted, people with lipodystrophy responded favorably to a twice-daily dose of 500 mg of metformin.^1,2)

Of all the fat distribution problems, peripheral fat loss and facial fat atrophy are the most troublesome to deal with. There is some evidence suggesting nucleoside analogs may contribute to the problem, Mulligan says. Preliminary data from France indicate that patients on stavudine (d4T) who are experiencing peripheral fat loss can mitigate the problem by substituting abacavir or zidovudine (AZT). However, the study is controversial and awaits independent confirmation.

Mulligan is involved in an AIDS Clinical Trials Group (ACTG) study getting underway early next year that will investigate the potential of a glitazone, a class of drugs approved for people with Type 2 diabetes, to restore peripheral fat and remove it from central regions. The trial will compare metformin with rosiglitazone maleate and will also compare a double combination of the two with a placebo.

Cohen is exploring the use of megestrol acetate, an antipregesterone agent, to increase fat. B vitamins, carnitines, and riboflavins have also been suggested as potential therapy for lipoatrophy, but there is little evidence to support their use, Cohen says.

Meanwhile, a number of patients are turning to cosmetic surgery to help with some of the complications, including facial wasting, for which some patients receive cheek implants. "I've heard that a number of patients here in San Francisco are doing that, but I don't think the medical community can endorse (it)," Mulligan says.

Cohen says until effective antidotes for lipodystrophy side effects are discovered, intermittent therapy may be one of the best ways to deal with the problem. "We've been able to stop and restart therapy before any AIDS-related complications can happen," he says. "I don't think it's a good thing to let HIV grow. Nonetheless if our therapies cause toxicity, we may be forced to choose the lesser of evils."

Meanwhile, several important studies on the horizon in the United States and Europe may yield information that will help physicians get a better handle on lipodystrophy in the future. Cohen believes randomized trials comparing nonnucleoside drugs to protease inhibitors and studies comparing nucleoside combinations may yield the answers to what causes some forms of lipodystrophy.

The ACTG has several studies planned or underway, including a survey of the long-term effects of antiretrovirals on metabolism and fat distribution. Another ACTG study will examine the efficacy of different drugs for treating hyperlipidemia and pharmacokinetic interactions between statin drugs and protease inhibitors. "Ultimately we'll have some ideas as to what combinations cause this more," Cohen says.

References

1. Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000 Jul 26;284(4):472-7.

2. Mascolini M. Shifty fat and bad bones (or, in vivo veritas). IAPAC Monthly 2000;6 (No. 11):326-350.

Louis Weisberg is editor-in-chief of Chicago Free Press. He can be reached at weisberg@chicagofreepress.com.

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